在眼咽肌萎缩症小鼠模型中,舌头的组织病理学标记提示生物力学缺陷。

IF 4.7 2区 医学 Q1 PATHOLOGY American Journal of Pathology Pub Date : 2025-01-10 DOI:10.1016/j.ajpath.2024.12.009
Rebecca Kordikowski Boix, Erik Bos, Milad Shademan, Sander Mallon, Sofie van Zanen-Gerhardt, Ngoc Lu-Nguyen, Alberto Malerba, Christina J J Coenen de Roo, Vered Raz
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引用次数: 0

摘要

舌头促进吞咽等重要活动。吞咽困难(吞咽困难)在老年人和许多成人发病的神经肌肉疾病中很常见。在眼咽肌营养不良症(OPMD),吞咽困难往往是第一症状。OPMD是一种常染色体显性肌病,由编码PABPN1基因的三核苷酸扩增突变引起。扩展的PABPN1形成不溶性的核聚集体,降低了可溶性形式的水平。临床舌头参与OPMD已被记录,但了解甚少。采用光镜、电镜结合RNA测序技术对OPMD小鼠舌部组织病理学进行研究。在4月龄小鼠中,发现了中等水平的PABPN1核聚集体,而血管中不溶性PABPN1的沉积已经很明显。舌头的肌肉萎缩与年龄有关。OPMD舌的线粒体和细胞骨架基因的RNA特征丰富。电镜显示A17/+组织中肌节和线粒体组织异常,提示OPMD舌部存在能量和收缩缺陷。对A17/+小鼠模型舌组织病理学的详细分析为理解吞咽困难的机制开辟了新的途径。
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Histopathologic Marks of Tongue in a Mouse Model of Oculopharyngeal Muscular Dystrophy Suggest Biomechanical Defects.

The tongue facilitates vital activities such as swallowing. Difficulty swallowing (dysphagia) is common in the elderly population and in patients with adult-onset neuromuscular disease. In oculopharyngeal muscular dystrophy (OPMD), dysphagia is often the first symptom. OPMD is an autosomal-dominant myopathy caused by a trinucleotide-expansion mutation in the gene encoding nuclear poly(A)-binding protein (PABPN)-1. Expanded-mutant PABPN1 forms insoluble nuclear aggregates that reduce the levels of the soluble form. Clinical tongue involvement in OPMD has been documented but is poorly understood. Histopathologic analysis of the tongue in an OPMD mouse model was done by light and electron microscopy combined with RNA sequencing. PABPN1 nuclear aggregates were found at moderate levels, whereas deposition of insoluble PABPN1 in blood vessels was prominent already at age 4 months. Muscle wasting of the tongue was age associated. RNA signatures of the OPMD tongue were enriched for mitochondrial and cytoskeletal genes. Electron microscopy revealed abnormalities in sarcomere and mitochondria organization in A17/+ mice, suggesting an energy and contractile deficit in OPMD tongue. This detailed analysis of the histopathology of the tongue in the A17/+ mouse model opens new avenues for understanding the mechanisms of dysphagia.

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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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